Overexpression of Ubiquitous Mitochondrial Creatine Kinase Denotes a Worse Prognosis for Gastric Cancer Patients

Abstract

Background: Ubiquitous mitochondrial creatine kinase (uMtCK) transfers high-energy phosphates from mitochondrially generated ATP to creatine to generate phosphocreatine. uMtCK overexpression has been reported in several malignant tumours, however, the clinical significance of uMtCK in gastric cancer (GC) has not been comprehensively studied. Methods: We first examined uMtCK expression in GC by qPCR and western blot. Then the clinicopathological significance of aberrant uMtCK expression was determined by immunohistochemical staining in a GC tissue microarray. Kaplan-Meier analysis was used for survival analysis. By virus transfection, we analyzed the biological function of uMtCK in GC cell in vivo and in vitro. Findings: uMtCK expression was substantially elevated in GC, significantly associated with a poor prognosis in GC patients. In univariate and multivariate analyses, uMtCK emerged as an independent prognostic factor for both disease-free survival and overall survival. In vitro, uMtCK overexpression increased GC cell proliferation, induced cell cycle transition, promoted cell migration and invasion. In vivo, uMtCK overexpression stimulated the formation of subcutaneous xenografts and tumour metastasis in nude mice. Moreover, we also revealed that high uMtCK expression promoted tumour chemoresistance to 5-fluorouracil chemotherapy. In the end, we verified that uMtCK activated the transforming growth factor-β signalling pathway, which was followed by increased levels of pSmad2 and pSmad3. Interpretation: uMtCK enhanced GC cell malignance via activating the transforming growth factor-β pathway, providing a novel independent prognostic biomarker for GC. Funding Statement: National Natural Science Foundation of China (81802420,81803073), Young Scientists of The Second Hospital of Shandong University (2018YT30). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: This research was approved by the Ethics Committee of Shanghai General Hospital. Written informed consent was obtained from all subjects, and they were subjected to close clinical follow-up observation.